What is the appropriate workup and management for abnormal liver function tests?

Workup and Management of Abnormal Liver Function Tests

Initial Laboratory Panel

Order a core liver panel consisting of bilirubin, albumin, ALT, ALP, and GGT, plus a complete blood count if not performed in the past 12 months. 1

• ALT is the most specific marker for hepatocellular injury and serves as the primary screening test 1
• Adding GGT to the panel doubles the sensitivity for detecting liver disease (from 15% to 30%), particularly for alcohol-related and non-alcoholic fatty liver disease, which together account for approximately 90% of liver-related mortality 1
• Do not routinely order AST in the initial panel—it did not improve disease detection in the BALLETS cohort analysis 1
• However, implement reflex AST testing on the same specimen when ALT or GGT is abnormal to calculate the AST:ALT ratio without requiring patient recall 1

Comprehensive Aetiology Screen

Any abnormality in the core panel—regardless of how modest—should trigger a complete aetiology workup. 1

Adult Standard Screen

The following tests should be ordered simultaneously 2:

• Abdominal ultrasound for structural assessment and detection of steatosis, masses, or biliary obstruction
• Hepatitis B surface antigen and hepatitis C antibody (with reflex PCR if positive)
• Anti-mitochondrial antibody to screen for primary biliary cholangitis
• Anti-smooth muscle antibody and antinuclear antibody for autoimmune hepatitis
• Serum immunoglobulins to detect hypergammaglobulinemia
• Simultaneous ferritin and transferrin saturation for iron overload evaluation

Pediatric Modifications

For children, modify the panel to include 2:

• Anti-liver kidney microsomal antibody
• Coeliac antibodies
• Alpha-1-antitrypsin level
• Caeruloplasmin (for children >3 years)

High-Risk Populations

In patients at elevated risk for viral hepatitis (injection drug users, migrants from high-prevalence regions, prisoners), order viral hepatitis screening simultaneously with the initial panel rather than sequentially to improve cost-effectiveness and avoid diagnostic delays. 1

Pattern Recognition and Risk Stratification

AST:ALT Ratio

An AST:ALT ratio >1 suggests advanced fibrosis or cirrhosis, even when both enzymes fall within the reference range. 1

This ratio remains a valuable risk-stratification tool and should be calculated whenever either enzyme is abnormal. 1

Hepatocellular vs. Cholestatic Pattern

• Hepatocellular injury: ALT/AST elevated >5× upper limit of normal, with ALP usually <2-3× upper limit of normal 3
• Cholestatic injury: ALP elevated 3-5× upper limit of normal, with only mild transaminase elevation 3
• The pattern of abnormality guides subsequent investigations more reliably than the absolute magnitude 1

Management Based on Common Etiologies

NAFLD (Most Common Cause)

For patients with echobright liver on ultrasound and no excessive alcohol use 2:

• Calculate FIB-4 score or NAFLD Fibrosis Score as first-line non-invasive fibrosis assessment
• Low-risk thresholds: FIB-4 <1.3 (age <65) or <2.0 (age ≥65); NFS <-1.455 (age <65) or <0.12 (age ≥65) can be managed in primary care 2
• Indeterminate scores: FIB-4 1.3-3.25 or NFS -1.455 to 0.675 require second-line testing such as enhanced liver fibrosis (ELF) test 2
• Primary treatment is calorie reduction and increased physical activity for gradual, sustained weight loss 2

Conditions Requiring Specialist Referral

Refer immediately for 2:

• Hepatitis B (HBsAg positive) or hepatitis C (antibody and PCR positive)
• Autoimmune hepatitis (raised IgG ± positive autoantibodies)
• Primary biliary cholangitis (cholestatic enzymes + positive anti-mitochondrial antibody)
• Primary sclerosing cholangitis (cholestatic enzymes ± inflammatory bowel disease history)
• Hemochromatosis (ferritin elevated AND transferrin saturation >45%)
• Dilated bile ducts on imaging (consider urgent referral depending on clinical context)

Critical Pitfalls to Avoid

• Normal ALT/AST does NOT exclude significant liver disease—cirrhosis can be present with completely normal enzymes 1
• Watchful waiting is inappropriate: 75% of patients with abnormal liver enzymes remain abnormal at 2 years, so any abnormality warrants investigation 1
• Isolated elevated ferritin is commonly seen in dysmetabolic iron overload syndrome (alcohol excess, NAFLD) and does not reflect hemochromatosis unless transferrin saturation is also >45% 2
• Neonatal cholestasis (conjugated bilirubin >25 μmol/L) requires urgent pediatric discussion 2
• Approximately 20% of patients have co-existing etiologies beyond the obvious cause, emphasizing the need for comprehensive screening 4

Prevalence Context

In the BALLETS study of 1,290 adults in primary care followed for 2 years 2:

• <5% had a specific disease affecting the liver
• Only 1.3% required immediate treatment (13 viral hepatitis, 4 hemochromatosis)
• Nearly 40% had fatty liver on ultrasound
• Country of origin (not ethnic group) was the strongest predictor of viral hepatitis
• Most patients with abnormal tests will have NAFLD or alcohol-related liver disease and can be managed in primary care with lifestyle modification and ongoing assessment